Evaluation of Endothelial-Mediated Mechanisms of Passive Leg Movement Hyperemia: Impact of Age and Exercise Training

Ageing uncompensated: exercise, nitric oxide and hypoxia

Cyclooxygenase (COX) contributes to cutaneous vasodilation and sweating responses; however, the mechanisms underpinning these responses remain unknown. We hypothesized that prostaglandin E1 (PGE1) and E2 (PGE2) (COX-derived vasodilator products) directly mediate cutaneous vasodilation and sweating through nitric oxide synthase (NOS)-dependent mechanisms in young adults. Furthermore, we hypothesized that this response is diminished in older adults, since aging attenuates COX-dependent cutaneous vasodilation and sweating. In 9 young (22 ± 5 yr) and 10 older (61 ± 6 yr) adults, cutaneous vascular conductance (CVC) and sweat rate were evaluated at four intradermal forearm skin sites receiving incremental doses (0.05, 0.5, 5, 50, 500 μM each for 25 min) of PGE1 or PGE2 with and without coadministration of 10 mM N(ω)-nitro-l-arginine, a nonspecific NOS inhibitor. N(ω)-nitro-l-arginine attenuated PGE1-mediated increases in CVC at all concentrations in young adults, whereas it reduced PGE2-mediated increases in CVC at lower concentrations (0.05-0.5 μM) in older adults (all P < 0.05). However, the magnitude of the PGE1- and PGE2-mediated increases in CVC did not differ between groups (all P > 0.05). Neither PGE1 nor PGE2 increased sweat rate at any of the administered concentrations for either the young or older adults (all P > 0.05). We show that although cutaneous vascular responsiveness to PGE1 and PGE2 is similar between young and older adults, the cutaneous vasodilator response is partially mediated through NOS albeit via low-to-high concentrations of PGE1 in young adults and low concentrations of PGE2 in older adults, respectively. We also show that in both young and older adults, PGE1 and PGE2 do not increase sweat rate under normothermic conditions.

Speechreading and Aging

To determine if age-associated vascular dysfunction in older adults with heart failure (HF) is due to insufficient synthesis of nitric oxide (NO), we performed two separate studies: 1) a kinetic study with a stable isotope tracer method to determine in vivo kinetics of NO metabolism, and 2) a vascular function study using a plethysmography method to determine reactive hyperemic forearm blood flow (RH-FBF) in older and young adults in the fasted state and in response to citrulline ingestion. In the fasted state, NO synthesis (per kg body wt) was ∼ 50% lower in older vs. young adults and was related to a decreased rate of appearance of the NO precursor arginine. Citrulline ingestion (3 g) stimulated de novo arginine synthesis in both older [6.88 ± 0.83 to 35.40 ± 4.90 μmol · kg body wt(-1) · h(-1)] and to a greater extent in young adults (12.02 ± 1.01 to 66.26 ± 4.79 μmol · kg body wt(-1) · h(-1)). NO synthesis rate increased correspondingly in older (0.17 ± 0.01 to 2.12 ± 0.36 μmol · kg body wt(-1) · h(-1)) and to a greater extent in young adults (0.36 ± 0.04 to 3.57 ± 0.47 μmol · kg body wt(-1) · h(-1)). Consistent with the kinetic data, RH-FBF in the fasted state was ∼ 40% reduced in older vs. young adults. However, citrulline ingestion (10 g) failed to increase RH-FBF in either older or young adults. In conclusion, citrulline ingestion improved impaired NO synthesis in older HF adults but not RH-FBF, suggesting that factors other than NO synthesis play a role in the impaired RH-FBF in older HF adults, and/or it may require a longer duration of supplementation to be effective in improving RH-FBF.

The sympathetic nervous system is an important regulator of coronary blood flow. The cold pressor test (CPT) is a powerful sympathoexcitatory stressor. We tested the hypotheses that: (1) CPT-induced sympathetic activation elicits coronary vasodilatation in young adults that is impaired with advancing age and (2) combined α- and β-adrenergic blockade diminishes/abolishes these age-related differences. Vascular responses of the left anterior descending artery to the CPT were determined by transthoracic Doppler echocardiography before (pre-blockade) and during (post-blockade) systemic co-administration of α- and β-adrenergic antagonists in young (n = 9; 26 ± 1 years old, mean ± SEM) and older healthy men (n = 9; 66 ± 2 years old). Coronary vascular resistance (CVR; mean arterial pressure/coronary blood velocity) was used as an index of vascular tone. CPT decreased CVR (i.e. coronary vasodilatation occurred) in young ( -33 ± 6%), but not older men ( -3 ± 4%; P < 0.05 vs. young) pre-blockade. Adrenergic blockade abolished CPT-induced coronary vasodilatation in young men ( -33 ± 6% vs. 0 ± 6%, pre-blockade vs. post-blockade, respectively; P < 0.05) such that responses post-blockade mirrored those of older men ( -3 ± 4% vs. 8 ± 9%; both P > 0.05 compared to young pre-blockade). Impaired CPT-induced coronary vasodilatation could not be explained by a reduced stimulus for vasodilatation as group and condition effects persisted when CVR responses were expressed relative to myocardial oxygen demand (rate-pressure product). These data indicate that the normal coronary vascular response to sympathetic activation in young men is pronounced vasodilatation and this effect is lost with age as the result of an adrenergic mechanism. These findings may help explain how acute sympathoexcitation may precipitate angina and coronary ischaemic events, particularly in older adults.

Redundancy reflects versatility of blood flow regulation mechanisms.

ABSTRACTMeaningful intergenerational interactions between older and younger adults are rare outside of family relationships. Interventions to increase positive intergenerational interactions are growing, but finding appropriate measures of attitudes toward both younger and older age groups is difficult. Many measures assessing attitudes toward older adults can remind participants of negative stereotypes of aging and are rarely used to assess attitudes toward younger adults. We adapted Pittinsky, Rosenthal, and Montoya’s allophilia measure to assess attitudes toward younger (18–25 years old) and older (over age 65) adults. In the first study, 94 traditional college age and 52 older adults rated older and younger adults. The allophilia measure distinguished between younger and older adults’ attitudes toward each age group. In the second study, we compared the age-related allophilia measures with seven traditional measures of attitudes toward older adults. Forty-seven traditional college age students completed measures. As predicted, correlations between allophilia toward older adults and the traditional semantic differential measures were weak (i.e., r = |0.15|or less), whereas correlations with general attitudes toward older adults were more moderate (r = 0.59 or less). Correlations between allophilia toward younger adults and the traditional measures were primarily non-significant as predicted. The allophilia measure differentiated between the five domains of positive attitudes toward younger and older adults and was not highly correlated with measures of more negative attitudes toward older adults. Results suggest that the allophilia measure can fill a need for a measure of positive attitudes toward older and younger adults.

The phenomenon of flow-mediated dilation (FMD) relevant to this debate describes the vasodilation in a conduit vessel in response to elevations in flow-associated shear stress. Nitric oxide (NO) is thought to play a key role in vascular health due to its established vasoprotective characteristics (

Functional Assessment in Younger and Older Adults with Sickle Cell Disease

Blocking nitric oxide (NO) and prostaglandin (PG) formation does not uniformly reduce radial artery (RA) flow mediated dilation (FMD) in young adults. We hypothesized that aging would alter these pathways such that blocking NO and PG would reduce RA FMD in older adults (n = 10 (5 men), 65±3 y). RA FMD was measured after brachial artery infusions of saline, N(G)‐ monomethyl‐L‐arginine (L‐NMMA), and ketorolac (KETO) + L‐NMMA. Data were compared to published data in young adults (n = 16 (8 men), 28±5 y). No sex differences were observed in either age group. L‐NMMA reduced FMD in older adults (8.9±3.6 to 5.9±3.7%) although this was not statistically significant (p = 0.08) and did not differ (p = 0.74) from the reduction observed in young adults (10.0±3.8 to 7.6±4.7%; p = 0.03). Shear stimulus normalization abolished the effect of L‐NMMA in both groups. No main or interaction effects of blocking PG on FMD were observed in young or older adults (p &gt;; 0.11). Heterogeneity was observed in dilatory responses to blockade in older adults. L‐NMMA reduced (n = 6; range = 36–123% decrease) or augmented FMD (n = 4; range = 0.4–122% increase). After PG blockade, reduced (48–103% decrease) and augmented (72–118% increase) FMD responses were observed. Contrary to our hypothesis, NO is not obligatory for RA FMD in older adults. Similar to young adults, redundant vasodilatory phenotypes exist in healthy, older humans. Funded by a HH Open Competition Grant

High Diagnostic Uncertainty and Inaccuracy in Adult Emergency Department Patients With Dyspnea: A National Database Analysis.

Blood flow and blood pressure are determined by an integration of reflex, humoral, and local vascular control mechanisms. Knowledge of these mechanisms has mushroomed over the past 15 years, particularly in the area of local endothelium-dependent vasomotor control. This has stemmed from the pioneering report in 1980 by Robert Furchgott1 demonstrating that the endothelium releases a vasodilator substance in response to acetylcholine. This concept has been expanded with knowledge that the endothelium releases a variety of relaxing and contracting factors that regulate the underlying smooth muscle.2 The most widely known endothelium-derived relaxing factor, nitric oxide, is released from endothelial cells in response to shear stress or stimulation of different receptors for a variety of neurohumoral mediators on the endothelial cell surface.3 The increase in endothelial cell calcium initiated by these stimuli increases the activity of a constitutively expressed enzyme, nitric oxide synthase, which converts l-arginine to nitric oxide and citrulline.4 5 6 7 Nitric oxide thus formed diffuses to and inhibits contraction of the underlying vascular smooth muscle.3 The physiological significance of the production of endothelial nitric oxide is suggested by the vasoconstriction observed in most vascular beds8 9 10 11 12 13 and the increase in systemic arterial blood pressure,14 15 16 which occurs on infusion of inhibitors of nitric oxide synthase. This observation further implies that under normal conditions, endothelial cells are locally liberating nitric oxide which effectively inhibits vasoconstriction arising by other mechanisms. Thus, normal vascular homeostasis depends in the periphery on a balance between neurally and humorally mediated vasoconstriction in skeletal muscle, mesentery, and the kidney, and local endothelium-dependent vasodilatation. In the truly vital areas of the heart, brain, and genitalia, vasodilator neural mechanisms reinforce the vasodilator influence of the endothelium.17 All is not known regarding the …

Passive leg movement is associated with a ∼3-fold increase in blood flow to the leg but the underlying mechanisms remain unknown. The objective of the present study was to examine the role of nitric oxide (NO) for the hyperaemia observed during passive leg movement. Leg haemodynamics and metabolites of NO production (nitrite and nitrate; NOx) were measured in plasma and muscle interstitial fluid at rest and during passive leg movement with and without inhibition of NO formation in healthy young males. The hyperaemic response to passive leg movement and to ACh was also assessed in elderly subjects and patients with peripheral artery disease. Passive leg movement (60 r.p.m.) increased leg blood flow from 0.3 ± 0.1 to 0.9 ± 0.1 litre min(-1) at 20 s and 0.5 ± 0.1 litre min(-1) at 3 min (P < 0.05). Mean arterial pressure remained unchanged during the trial. When passive leg movement was performed during inhibition of NO formation (N(G)-mono-methyl-l-arginine; 29-52 mg min(-1)), leg blood flow and vascular conductance were increased after 20 s (P < 0.05) and then returned to baseline levels, despite an increase in arterial pressure (P < 0.05). Passive leg movement increased the femoral venous NOx levels from 35 ± 5 at baseline to 62 ± 11 μmol l(-1) during passive leg movement (P < 0.05), whereas muscle interstitial NOx levels remained unchanged. The hyperaemic response to passive leg movement were correlated with the vasodilatation induced by ACh (r(2) = 0.704, P < 0.001) and with age (r(2) = 0.612, P < 0.001). Leg blood flow did not increase during passive leg movement in individuals with peripheral arterial disease. These results suggest that the hypaeremia induced by passive leg movement is NO dependent and that the source of NO is likely to be the endothelium. Passive leg movement could therefore be used as a non-invasive tool to evaluate NO dependent endothelial function of the lower limb.

Effective processing of multisensory stimuli relies on both the peripheral sensory organs and central processing in subcortical and cortical structures. As we age, there are significant changes in all sensory systems and a variety of cognitive functions. Visual acuity tends to decrease and hearing thresholds generally increase (Kalina 1997; Liu and Yan 2007), whereas performance levels on tasks of motor speed, executive function, and memory typically decline (Rapp and Heindel 1994; Birren and Fisher 1995; Rhodes 2004). There are also widespread changes in the aging brain, including reductions in gray and white matter volume (Good et al. 2001; Salat et al. 2009), alterations in neurotransmitter systems (Muir 1997; Backman et al. 2006), regional hypoperfusion (Martin et al. 1991; Bertsch et al. 2009), and altered patterns of functional activity during cognitive tasks (Cabeza et al. 2004; Grady 2008). Given the extent of age-related alterations in sensation, perception, and cognition, as well as in the anatomy and physiology of the brain, it is not surprising that multisensory integration also changes with age.Several early studies provided mixed results on the differences between multisensory processing in older and younger adults (Stine et al. 1990; Helfer 1998; Strupp et al. 1999; Cienkowski and Carney 2002; Sommers et al. 2005). For example, Stine and colleagues (1990) reported that although younger adults’ memory for news events was better after audiovisual presentation than after auditory information alone, older adults did not show improvement during the multisensory conditions. In contrast, Cienkowski and Carney (2002) demonstrated that audiovisual integration on the McGurk illusion was similar for older and younger adults, and that in some conditions, older adults were even more likely to report the fusion of visual and auditory information than their young counterparts. Similarly, in a study examining the contribution of somatosensory input to participants’ perception of visuospatial orientation, Strupp et al. (1999) reported an age-related increase in the integration of somatosensory information into the multisensory representation of body orientation.Despite providing a good indication that multisensory processing is somehow altered in aging, the results of these studies are somewhat difficult to interpret due to their use of complex cognitive tasks and illusions, and to the variability in analysis methods. Several newer studies that have attempted to address these factors more clearly demonstrate that multisensory integration is enhanced in older adults (Laurienti et al. 2006; Peiffer et al. 2007; Diederich et al. 2008).On a two-choice audiovisual discrimination task, Laurienti and colleagues (2006) showed that response time (RT) benefits for multisensory versus unisensory targets were larger for older adults than for younger adults (Figure 20.1). That is, older adults’ responses during audiovisual conditions were speeded more than younger adults’, when compared with their respective responses during unisensory conditions. Multisensory gains in older adults remained significantly larger than those observed in younger adults, even after controlling for the presence of two targets in the multisensory condition (redundant target effect; Miller 1982, 1986; Laurienti et al. 2006).Using similar analysis methods, Peiffer et al. (2007) also reported increased multisensory gains in older adults. On a simple RT task, where average unisensory RTs were equivalent in younger and older adults, older adults actually responded faster than younger adults on multisensory trials because of their enhanced multisensory integration (Peiffer et al. 2007). Diederich and colleagues (2008) have also shown that older adults exhibit greater speeding of responses to multisensory targets than younger adults on a saccadic RT task. The analysis methods used in this experiment indicate a slowing of peripheral sensory processing, as well as a wider time window over which integration of auditory and visual stimuli can occur (Diederich et al. 2008).These experiments highlight several possible explanations that could help answer a critical question about multisensory processing in aging: Why do older adults exhibit greater integration of multisensory stimuli than younger adults? Potential sources of enhanced integration in older adults include age-related cognitive slowing not specific to multisensory processing, inverse effectiveness associated with sensory deficits, alterations in the temporal parameters of integration, and inefficient top–down modulation of sensory processing. In the following sections we will investigate each of these possible explanations in greater detail and offer some alternative hypotheses for the basis of enhanced multisensory integration in older adults.

We tested the hypothesis that reduced nitric oxide (NO) bioavailability contributes to the attenuated peak and total vasodilation following single muscle contractions in older adults. Young (n=8; 25 ± 2 yr) and older (n=9; 67 ± 2 yr) adults performed single forearm contractions at 10, 20 and 40% of maximum during saline infusion (control) and NO synthase (NOS) inhibition via L‐NMMA. Brachial artery diameter and velocities were measured using Doppler ultrasound and forearm vascular conductance (FVC) was calculated from blood flow (ml/min) and blood pressure (mmHg). Peak and total vasodilator responses (ΔFVC from baseline) were attenuated in older adults at all intensities (P &lt; 0.05). NOS inhibition reduced the peak ΔFVC at 10% (95 ± 13 vs. 59 ± 10), 20% (134 ± 11 vs. 90 ± 12) and 40% (222 ± 30 vs. 143 ± 24) in young subjects (P &lt; 0.05 for all) and in older adults at 10% (61 ± 5 vs. 48 ± 7, P &lt; 0.05) and 20% (90 ± 8 vs. 70 ± 8, P &lt; 0.05), but not 40% (129 ± 13 vs. 105 ± 11, P = 0.12). The relative (%) reduction in peak ΔFVC due to NOS inhibition was greater in young vs. older adults at 20% (−36 ± 5 vs. −22 ± 5%, P &lt; 0.05) and 40% (−35 ± 7 vs. −17 ± 7%, P &lt; 0.05). The reduction in the total vasodilator response (area under the curve) with NOS inhibition was also greater in young vs. older adults at 20 and 40%. Our data suggest that contraction‐induced rapid vasodilation is mediated in part by NO; however, it appears the NO contribution in the response is greater in young adults.